Bone is a dynamic tissue, and homeostasis in the adult skeleton requires a balance between bone resorption and bone formation. Osteoclasts and osteoblasts play a key role in this balance, with osteoclasts initiating bone resorption and osteoblasts synthesizing and depositing new bone matrix. Imbalances in bone homeostasis are associated with such disorders as osteoporosis, Paget's disease, and hyperparathyroidism.
The activities of osteoclasts and osteoblasts are regulated by complex interactions between systemic hormones such as calcitonin and the local production of growth factors and cytokines. Calcitonin, a peptide hormone secreted by the thyroid and thymus of mammals, plays an important role in maintaining bone homeostasis. Calcitonin inhibits bone resorption through binding and activation of a specific calcitonin receptor on osteoclasts [M. Pondel, Calcitonin and Calcitonin Receptors: Bone and Beyond, Int. J. Exp. Path. 81, 405-22 (2000)], with a resultant decrease in the amount of calcium released by bone into the serum. This inhibition of bone resorption has been exploited, for instance, by using calcitonin as a treatment for osteoporosis, a disease characterized by a decrease in the skeletal mass often resulting in debilitating and painful fractures. Calcitonin is also used in the treatment of Paget's disease where it provides rapid relief from bone pain, which is frequently the primary symptom associated with this disease. This analgesic effect has also been demonstrated in patients with osteoporosis or metastatic bone disease and has been reported to relieve pain associated with diabetic neuropathy, cancer, migraine and post-hysterectomy. Reduction in bone pain occurs before the reduction of bone resorption.
Despite the frequent use of animal-derived calcitonin in humans (such as salmon calcitonin), there are many disadvantages. For treatment of osteoporosis, for instance, daily prophylactic administration can be required for 5 or more years at a relatively high cost. In the United States, calcitonin is often administered by injection, and since the disease indications for this drug are not usually life threatening, patient compliance can be low. Resistance to calcitonin therapy may occur with long-term use. In addition, some patients develop antibodies to non-human calcitonin. Such disadvantages have spurred the search for small-molecule replacements for calcitonin.
Amylin and adrenomedullin are related peptides with some homology to both calcitonin and calcitonin gene-related peptide. [P M. Sexton et al., Curr. Med. Chemistry, 1999, 6:1067] Like the peptides themselves, the receptors for the calcitonin family are related to each other. Each peptide acts through its own distinct high affinity receptor, as well as through other receptors of the family, usually with lower affinity. Amylin and adrenomedullin have recently been found to stimulate the proliferation of osteoblasts in vitro, and to increase indices of bone formation when administered either locally or systemically in vivo. Furthermore, amylin inhibits bone resorption. [Cornish, J. et al., Curr. Pharm. Des., 2002, 8(23):2009]. In addition to its bone-effects, however, amylin also has an important role in postprandial glucose regulation. The neuroendocrine hormone is cosecreted with insulin at mealtimes and has been shown to suppress postprandial glucagon secretion [Gedulin, B. et al., Metabolism, 1997, 46:67], to regulate gastric emptying [Young, A. et al., Diabetologia, 1995, 38:642] and to reduce food intake [Rushing et al., Endocrinology, 2000, 141:850]. Because of these effects, the peptide and related analogues such as pramlintide are being investigated for the treatment of diabetes. Similar to calcitonin, the drawback to this peptidic approach is the need for administration by injection, resulting in potentially reduced patient compliance and high costs of production.